Arylthiadiazole derivative and antiviral agent containing the same

ABSTRACT

Novel arylthiadiazole derivatives and salts thereof useful for preventing and treating human viral infection and a novel virucide which contains the arylthiadiazole derivative or a salt thereof are provided. N,N-dimethyl  3-(3-(amino-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate or its salt, and virucide containing the same as an effective component.

This application is a 371 of PCT/JP95/01898 filed on Sep. 21, 1995

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to arylthiadiazole derivatives and salts thereof having antiviral activity.

2. Description of the Related Art

Thiadiazoles having herbicidal activity are described in JP-A-3-193773, JP-A-4-103575, and JP-A-4-117372. Thiadiazoles useful as an agricultural fungicide are described in JP-A-4-182403, and JP-A-4-182405. On the other hand, acyclovir (antiherpetic medicine), amantadine (antiinfluenzal medicine), azidothymidine (anti-HIV medicine, HIV: human immunodeficiency virus) are known as antiviral medicines.

No medicine is effective against viral diseases at the moment, so that effective antiviral medicines are desired to be developed. In particular, development of anti-HIV medicine is urgent.

DISCLOSURE OF THE INVENTION

After comprehensive investigation, it was found by the inventors of the present invention that arylthiadiazole derivatives have excellent antiviral activity. Based on the findings, the present invention has been accomplished.

The present invention provides arylthiadiazole derivatives represented by General Formula I!, and salts thereof: ##STR1## where Y¹ is an oxygen atom or a sulfur atom; W is an oxygen atom or a sulfur atom; one of R¹, R², and R³ is an amino group which may be substituted by one or two independent alkyls of 1-6 carbons; a carboxyl group; a carbonyl group which is substituted by an alkoxyl of 1-4 carbons; a carbamoyl group which may be substituted by one or two independent alkyls of 1-6 carbons; a cyano group; or an alkyl group of 1-6 carbons which is substituted by a hydroxyl, an alkoxyl of 1-4 carbons, an alkoxyl of 1-4 carbons (which is further substituted by another alkoxyl of 1-4 carbons), or a silyloxy group (which is substituted by three independent alkyls of 1-6 carbons); the other two of R¹, R², and R³ are independently a hydrogen atom; a halogen atom; an alkyl group of 1-6 carbons which may be substituted by a hydroxyl, an alkoxyl of 1-4 carbons, an alkoxyl of 1-4 carbons (which is further substituted by another alkoxyl of 1-4 carbons), or a silyloxy (which is substituted by three independent alkyls of 1-6 carbons; a trifluoromethyl group; an alkoxyl group of 1-4 carbons; a carboxyl group; a carbonyl group which is substituted by an alkoxyl of 1-4 carbons; a carbamoyl group which may be substituted by one or two independent alkyls of 1-6 carbons; a cyano group; a hydroxyl group; a hydroxymethyl group; a nitro group; or an amino group which may be substituted by one or two independent alkyls of 1-6 carbons; R⁴, and R⁵ are independently a hydrogen atom, an alkoxyl group of 1-4 carbons, an alkyl group of 1-6 carbons which may be substituted by an alkoxyl of 1-4 carbons, a hydroxyl, a cyano, a carboxyl, a carbamoyl, a carbonyl (substituted by alkoxyl of 1-4 carbons), or a group of ##STR2## or R⁴ and R⁵ are linked together to form a group of ##STR3## R⁶, R⁷, and R⁸ are independently a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbons, or an alkoxyl group of 1-4 carbons; R⁹, and R¹⁰ are independently a hydrogen atom, or an alkyl group of 1-6 carbons; E is a --CH₂ -- or an oxygen atom; and n¹ is an integer of 0 to 2.

The present invention also provides a virucide containing the arylthiadiazole derivative represented by General Formula I! or the salt thereof as an active ingrdient.

The present invention further provides arylthiadiazole derivatives represented by the formulas below, and salts thereof: ##STR4## where n² is 1 or 2; n³ is 0 or 1;

Y¹ is an oxygen atom or a sulfur atom;

W is an oxygen atom or a sulfur atom;

R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group;

R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group (which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons);

R¹⁸ is an alkyl group of 1-6 carbons which is substituted by a hydroxyl, a cyano, a carboxyl, a carbamoyl, or a carbonyl substituted by an alkoxyl group of 1-4 carbons;

R¹⁹ is a hydrogen atom, or an alkyl group of 1-6 carbons which may be substituted by an alkoxyl of 1-4 carbons;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, E, and n¹ are the same as mentioned above, provided that, in the last formula, R¹¹, R¹², and R¹³ are not simultaneously a hydrogen atom when n³ is 0.

The present invention further provides a virucide containing an arylthiadiazole of General Formula II!, or a salt thereof as an active ingredient: ##STR5## where A is a group of ##STR6## where R¹⁵, and R¹⁶ are independently a hydrogen atom, a halogen atom, an alkoxyl group of 1-4 carbons, a nitro group, or an alkyl group of 1-6 carbons which may be substituted with a halogen;

J is --CH═, or --N═;

Y² is an oxygen atom, a sulfur atom, or --NR¹⁴ --;

R¹⁷ is a halogen atom, or NR¹⁴ --R¹⁹ ; and

R¹¹, R¹², R¹³, R¹⁴, R¹⁸, R¹⁹, n², n³, R⁴, R⁵, R⁹, R¹⁰, R¹⁴, Y¹, and W are the same as mentioned above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is described in more detail.

The alkyl group of 1-6 carbons as the substituent in General Formulas I! and II! includes linear, branched, or cyclic alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl. The alkoxyl group of 1-4 carbons includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, and t-butoxy. The halogen atoms includes atoms of fluorine, chlorine, bromine, and iodine.

Typical production processes are shown for the arylthiadiazole derivative represented by General Formula I! or II!.

Production Process 1 ##STR7## where Q is a chlorine, bromine, or iodine atom; R¹, R², R³, R⁴, R⁵, Y¹, and W are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula I! can be produced by reaction of a derivative represented by General Formula III! with a carbamoyl derivative represented by General Formula IV!.

The reaction is conducted in a solvent in the presence of a base at a temperature of from 0 to 150° C., preferably from 20 to 100° C., for several minutes to 24 hours, preferably from 1 to 12 hours.

The carbamoyl derivative of General Formula IV! is used in an amount of 1-5 equivalents, preferably 1-3 equivalents, and the base is used in an amount of 1-5 equivalents, preferably 1-3 equivalents, to one equivalent of the derivative of General Formula III!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, and t-butanol; water, and the like.

The base includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

(Production Process 1-1)

The arylthiadiazole derivative of General Formula I! in which at least one of R¹, R², and R³ is an alkyl group of 1-6 carbons substituted by a hydroxyl group, and R⁴, R⁵, Y¹, and W are the same as defined above can be produced by hydrolysis of the arylthiadiazole of General Formula I! in which at least one of R¹, R², and R³ is an alkyl group of 1-6 carbons which is substituted by an alkoxyl of 1-4 carbons, an alkoxyl of 1-4 carbons (which is further substituted by another alkoxyl of 1-4 carbons), or a silyloxy (which is further substituted by three independent alkyls of 1-6 carbons)!, and R⁴, R⁵, Y¹, and W are the same as mentioned above.

The reaction is conducted in a solvent in the presence of an acid or a base at a temperature of from 0 to 120° C., preferably from 20 to 100° C., for several minutes to 12 hours, preferably from 1 to 6 hours.

The acid or the base is used in an amount of 1-50 equivalents, preferably 1-20 equivalents to one equivalent of the substrate substance.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, t-butanol; water, and the like.

The base includes inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The acid includes protonic acids such as acetic acid, trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, and sulfuric acid; and Lewis acids such as aluminum chloride, titanium tetrachloride, boron trifluoride, boron tribromide, zinc bromide, trimethylsilyl iodide, and tetrabutylammonium fluoride.

(Production Process 1-2)

The arylthiadiazole derivative of General Formula I! in which at least one of R¹, R², and R³ is a carboxyl group, and R⁴, R⁵, Y¹, and W are the same as defined above can be produced by hydrolysis of the arylthiadiazole of General Formula I! in which at least one of R¹, R², and R³ is a carbonyl group substituted by an alkoxyl of 1-4 carbons, and R⁴, R⁵, Y¹, and W are the same as mentioned above.

The reaction is conducted in a solvent in the presence of an acid or a base at a temperature of from 0 to 120° C., preferably from 20 to 100° C., for several minutes to 12 hours, preferably from 1 to 6 hours.

The acid or the base is used in an amount of 1 to 50 equivalents, preferably 1 to 20 equivalents to one equivalent of the substrate substance.

The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, and t-butanol; water, and the like.

The base includes inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The acid includes acetic acid, trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trimethylsilyl chloride, boron tribromide, aluminum chloride, and the like.

(Production Process 1-3)

The arylthiadiazole derivative of General Formula I! in which at least one of R¹, R², and R³ is an amino group which may be substituted by one or two independent alkyls of 1-6 carbons, and R⁴, R⁵, Y¹, and W are the same as defined above can be produced by reduction, with hydrogen, of the arylthiadiazole derivative of General Formula I! in which at least one of R¹, R², and R³ is a nitro group, and R⁴, R⁵, Y¹, and W are the same as mentioned above in the presence of a catalyst such as platinum oxide, platinum, platinum-carbon, platinum sulfide-carbon, and palladium-carbon. Further, the amino group can be alkylated by reaction of the resulting amino group with an alkylating agent of 1-6 carbons, if necessary.

The reduction reaction is conducted in a solvent in the presence or absence of an acid at a temperature of from 0 to 80° C., preferably from 10 to 50° C., for several minutes to 24 hours, preferably from 1 to 12 hours.

The catalyst is used in an amount of 0.01 to 1 part, preferably 0.03 to 0.3 part by weight, and the acid is used in an amount of 0.1 to 10 parts, preferably 0.5 to 3 parts by weight to one part by weight of the substrate substance. The hydrogen pressure is 1 to 5 atmosphere, preferably 1 to 2 atmosphere.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, acetonitrile and ethyl acetate; alcohols such as methanol, ethanol, isopropanol, and t-butanol; acetic acid; water, and the like.

The catalyst includes platinum oxide, platinum, platinum-carbon, platinum sulfide-carbon, palladium-carbon, and the like.

The acid includes acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, trifluoroacetic acid, and the like.

The alkylation of the resulting amino group is conducted by reaction with an alkylating agent of 1-6 carbons in a solvent in the presence or absence of a base at 0 to 130° C., preferably 20 to 100° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The alkylating agent of 1-6 carbons is used in an amount of 0.5 to 5 equivalents, preferably 1 to 3 equivalents, to one equivalent of the substrate substance.

The alkylating agent includes alkyl halides, alkyl sulfate esters, and the like.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, acetonitrile and ethyl acetate; alcohols such as methanol, ethanol, isopropanol, and t-butanol; amines such as pyridine, triethylamine, and N,N-diisopropylethylamine; water, and the like.

The base includes organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

Production Process 2 ##STR8## where R¹, R², R³, R⁴, R⁵, Y¹, and W are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula I! can be produced by reaction of a derivative represented by General Formula III! with a carbonylating agent, and subsequent reaction with an amine represented by General Formula V!.

The carbonylation is conducted in a solvent in the presence or absence of a base at 0 to 100° C., preferably 10 to 50° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The carbonylating agent is used in an amount of 1 to 3 equivalents, preferably 1 to 2 equivalents, and the base is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents to one equivalent of the derivative represented by General Formula III!.

The carbonylating agent includes phosgene, thiophosgene, trichloromethyl chloroformate, bis(trichloromethyl) carbonate, 1,1'-thiocarbonyldiimidazole, 1,1'-carbonyldiimidazole, dimethyl carbonate, and the like.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and the like.

The base includes organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The subsequent reaction with the amine represented by General Formula V! is conducted in a solvent in the presence or absence of a base at 0 to 100° C., preferably 10 to 50° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The amine of General Formula V! is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents to one equivalent of the derivative represented by General Formula III!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and the like.

The base includes organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

Production Process 3 ##STR9## where R¹, R², R³, R⁴, Y¹ and W are the same as mentioned above.

The arylthiadiazole represented by General Formula I-a! can also be produced by reaction of a derivative represented by General Formula III! with an isocyanate represented by General Formula VI!.

The reaction is conducted in a solvent in the presence or absence of a base at 0 to 150° C., preferably 20 to 100° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The isocyanate represented by General Formula VI! is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, and the base is used in an amount of 0.01 to 3 equivalents, preferably 0.01 to 1 equivalent to one equivalent of the derivative represented by General Formula III!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; and polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, acetonitrile, and the like.

The base includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

Production Process 4 ##STR10## where R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula II-a! can be produced by reaction of an amide derivative represented by General Formula VII! with phosphorus oxychloride, and subsequent reaction with an amine derivative represented by General Formula VIII!.

The reaction with phosphorus oxychloride is conducted in a solvent at 0 to 100° C., preferably from 10 to 50° C., for several minutes to 24 hours, preferably 3 to 12 hours.

The phosphorus oxychloride is used in an amount of from 0.3 to 1.5 equivalents, preferably from 0.5 to 1.1 equivalents to one equivalent of the amide derivative represented by General Formula VII!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and the like.

The subsequent reaction with the amine derivative represented by General Formula VIII! is conducted in the same solvent used for the reaction with phosphorus oxychloride at 10 to 130° C., preferably 50 to 90° C., for several minutes to 12 hours, preferably 1 to 6 hours.

The amine derivative represented by General Formula VIII! is used in an amount of 0.25 to 1 equivalent, preferably 0.5 to 1.0 equivalent to 1 equivalent of the amide derivative represented by General Formula VII!.

Production Process 5 ##STR11## where R¹¹, R¹², R¹³, n³, and Q are the same as mentioned above.

The carboxylic acid derivative represented by General Formula X! can be produced by reaction of a halogen compound represented by General Formula IX! with a cyanating agent, and subsequent hydrolysis by an acid or a base.

The reaction with the cyanating agent is conducted in a solvent at 10 to 180° C., preferably 50 to 150° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The cyanating agent is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents to one equivalent of the halogen compound represented by General Formula IX!.

The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, acetonitrile, and the like.

The cyanating agent includes sodium cyanide, potassium cyanide, copper cyanide, and the like.

The subsequent hydrolysis reaction is conducted in a solvent in the presence of an acid or a base at 0 to 120° C., preferably 20 to 100° C., for several minutes to 12 hours, preferably 1 to 6 hours.

The acid or the base is used in an amount of from 1 to 50 equivalents, preferably 1 to 20 equivalents, to one equivalent of the substrate substance.

The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, and t-butanol; water, and the like.

The base includes inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The acid includes formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

Production Process 6 ##STR12## where R⁴, R⁵, R¹¹, R¹², R¹³, and n³ are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula II-b! can be produced by reaction of a carboxylic acid derivative represented by General Formula X! with a chlorinating agent to form an acid chloride represented by General Formula XI!, and subsequent reaction with an amine represented by General Formula V!.

The reaction with the chlorinating agent is conducted without a solvent or in a solvent at 0 to 100° C., preferably 10 to 80° C., for several minutes to 12 hours, preferably 1 to 6 hours.

The chlorinating agent is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents to one equivalent of the carboxylic acid derivative represented by General Formula X!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; and polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and the like.

The chlorinating agent includes thionyl chloride, oxalyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, and the like.

A brominating agent or an iodinating agent can be used in place of the chlorinating agent for the reaction.

The subsequent reaction with the amine represented by General Formula V! is conducted in a solvent in the presence or absence of a base at 0 to 50° C., preferably 0 to 20° C., for several minutes to 6 hours, preferably 0.5 to 2 hours.

The amine represented by General Formula V! is used in an amount of from 1 to 5 equivalents, preferably from 1 to 2 equivalents, and the base is used in an amount of from 1 to 5 equivalents, preferably 1 to 3 equivalents, to one equivalent of the acid chloride represented by General Formula XI!.

The base includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The solvent includes hydrocarbons.such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; water, and the like.

Production Process 7 ##STR13## where R⁴, R⁵, R¹¹, R¹², R₁₃, and n³ are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula II-c! can be produced by reaction of an arylthiadiazole derivative represented by General Formula II-b! with a sulfidizing agent.

The reaction is conducted in a solvent at 20 to 150° C., preferably 50 to 100° C., for several minutes to 6 hours, preferably 0.5 to 2 hours.

The sulfidizing agent is used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents to one equivalent of the arylthiadiazole derivative represented by General Formula II-b!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; and amines such as pyridine, triethylamine, and the like.

The sulfidizing agent includes phosphorus pentasulfide, Lawesson's Reagent, and the like.

Production Process 8 ##STR14## where R¹¹, R¹², R¹³, R¹⁷, Y¹, and n² are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula II-d! can be produced by reaction of a derivative represented by General Formula XII! with a halogen compound represented by General Formula XIII!.

The reaction is conducted in a solvent in the presence of a base at 0 to 150° C., preferably 20 to 100° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The halogen compound represented by General Formula XIII! is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, to one equivalent of the derivative represented by General Formula XII!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, and t-butanol; water, and the like.

The base includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

Production Process 9 ##STR15## where R¹¹, R¹², R¹³, R¹⁹, Y¹, Y², n², and Q are the same as mentioned above.

The arylthiadiazole derivative represented by General Formula II-f! can be produced by reaction of an arylthiadiazole derivative represented by General Formula II-e! with a compound represented by General Formula XIV!.

The reaction is conducted in a solvent in the presence of a base at 0 to 150C., preferably 20 to 100° C., for several minutes to 24 hours, preferably 1 to 12 hours.

The compound represented by General Formula XIV! is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, to one equivalent of the arylthiadiazole derivative represented by General Formula II-e!.

The solvent includes hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; amines such as pyridine, and triethylamine; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, and t-butanol; water, and the like.

The base includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

Production Process 10 ##STR16## where R¹¹, R¹², R¹³, R¹⁴, R¹⁸, Y¹, and W are the same as mentioned above. The arylthiadiazole derivative represented by General Formula II-g! can be produced in a similar manner as in Production Process 1, 2, or 3.

(Production Process 10-1)

The arylthiadiazole derivative of General Formula II-g! in which R¹⁸ is an alkyl group of 1 to 6 carbons substituted by a carboxyl or carbamoyl group, and R¹¹, R¹², R¹³, R¹⁴, Y¹, and W are the same as mentioned above can be produced by hydrolysis of the arylthiadiazole derivative represented by General Formula II-g! in which R¹⁸ is an alkyl group of 1 to 6 carbons substituted by a cyano group, and R¹¹, R¹², R¹³, R¹⁴, Y¹, and W are the same as above.

The reaction is conducted in a solvent in the presence of an acid or a base at 0 to 120° C., preferably 20 to 100° C., for several minutes to 12 hours, preferably 1 to 6 hours.

The acid or the base is used in an amount of 1 to 50 equivalents, preferably 1 to 20 equivalents, to one equivalent of the substrate substance.

The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, t-butanol; water, and the like.

The base includes inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like.

The acid includes formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

(Production Process 10-2)

The arylthiadiazole derivative of General Formula II-g! in which R¹⁸ is an alkyl group of 1 to 6 carbons which is substituted by a carbonyl group substituted by an alkoxyl group of 1 to 4 carbons, and R¹¹, R¹², R¹³, R¹⁴, Y¹, and W are the same as mentioned above can be produced by reaction, with an alcohol of 1 to 4 carbons, of the arylthiadiazole derivative represented by General Formula II-g! in which R¹⁸ is an alkyl group of 1 to 6 carbons substituted by a carboxyl group, and R¹¹, R¹², R¹³, R¹⁴, Y¹ and W are the same as above.

The reaction is conducted in a solvent in the presence of an acid at 0 to 120° C., preferably 20 to 100° C., for several minutes to 12 hours, preferably 1 to 6 hours.

The acid is used in an amount of 1 to 50 equivalents, preferably 1 to 20 equivalents to one equivalent of the substrate substance.

The solvent includes ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and acetonitrile; alcohols such as methanol, ethanol, isopropanol, t-butanol; water, and the like.

The acid includes formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

Specific examples of the arylthiadiazole derivatives represented by General Formula I! or II! are shown in Tables 1 to 26. However, the present invention is not limited thereto.

                  TABLE 1                                                          ______________________________________                                         1 #STR17##                                                                     Compound                                                                       No.     R.sup.1                                                                              R.sup.2                                                                              R.sup.3                                                                              Y.sup.1                                                                              W    NR.sup.4 R.sup.5                          ______________________________________                                         1       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              2 #STR18##                                2       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              3 #STR19##                                3       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              4 #STR20##                                4       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              5 #STR21##                                5       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              6 #STR22##                                6       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              7 #STR23##                                7       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              8 #STR24##                                8       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              9 #STR25##                                9       H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              0 #STR26##                                10      H     H     2-NH.sub.2                                                                           --O-- ═O                                                                              1 #STR27##                                ______________________________________                                    

                                      TABLE 2                                      __________________________________________________________________________     1 #STR28##                                                                     Compound No.                                                                          R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                            Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                         __________________________________________________________________________     11     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            2 #STR29##                                               12     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            3 #STR30##                                               13     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            4 #STR31##                                               14     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            5 #STR32##                                               15     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            6 #STR33##                                               16     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            7 #STR34##                                               17     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            8 #STR35##                                               18     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            9 #STR36##                                               19     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            0 #STR37##                                               20     H H 2-NH.sub.2                                                                         --O--                                                                              ═O                                                                            1 #STR38##                                               __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________     1 #STR39##                                                                     Compound No.                                                                          R.sup.1                                                                          R.sup.2                                                                           R.sup.3 Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                    __________________________________________________________________________     21     H 2-Cl                                                                              5-NH.sub.2                                                                             --O--                                                                              ═O                                                                            2 #STR40##                                          22     H 2-Cl                                                                              5-NH.sub.2                                                                             --O--                                                                              ═O                                                                            4 #STR41##                                          23     H 2-Cl                                                                              5-NH.sub.2                                                                             --O--                                                                              ═O                                                                            9 #STR42##                                          24     H 2-Cl                                                                              5-NHMe  --O--                                                                              ═O                                                                            4 #STR43##                                          25     H 2-Cl                                                                              5-NHMe  --O--                                                                              ═O                                                                            9 #STR44##                                          26     H 2-Cl                                                                              5-NMe.sub.2                                                                            --O--                                                                              ═O                                                                            4 #STR45##                                          27     H 2-Cl                                                                              5-NMe.sub.2                                                                            --O--                                                                              ═O                                                                            9 #STR46##                                          28     H 2-Cl                                                                              5-CH.sub.2 OCH.sub.2 OMe                                                               --O--                                                                              ═O                                                                            4 #STR47##                                          29     H 2-Cl                                                                              5-CH.sub.2 OCH.sub.2 OMe                                                               --O--                                                                              ═O                                                                            9 #STR48##                                          30     H 2-Cl                                                                              5-CH.sub.2 OSiMe.sub.3                                                                 --O--                                                                              ═O                                                                            4 #STR49##                                          __________________________________________________________________________

                                      TABLE 4                                      __________________________________________________________________________     1 #STR50##                                                                     Compound No.                                                                          R.sup.1                                                                          R.sup.2                                                                           R.sup.3                                                                               Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                     __________________________________________________________________________     31     H 2-Cl                                                                              5-CH.sub.2 OSiMe.sub.2                                                                --O--                                                                              ═O                                                                            9 #STR51##                                           32     H 2-Cl                                                                              5-CH.sub.2 OH                                                                         --O--                                                                              ═O                                                                            4 #STR52##                                           33     H 2-Cl                                                                              5-CH.sub.2 OH                                                                         --O--                                                                              ═O                                                                            9 #STR53##                                           34     H 2-Cl                                                                              5-CN   --O--                                                                              ═O                                                                            4 #STR54##                                           35     H 2-Cl                                                                              5-CN   --O--                                                                              ═O                                                                            9 #STR55##                                           36     H 2-Cl                                                                              5-CO.sub.2 H                                                                          --O--                                                                              ═O                                                                            4 #STR56##                                           37     H 2-Cl                                                                              5-CO.sub.2 H                                                                          --O--                                                                              ═O                                                                            9 #STR57##                                           38     H 2-Cl                                                                              5-CO.sub.2 Me                                                                         --O--                                                                              ═O                                                                            4 #STR58##                                           39     H 2-Cl                                                                              5-CO.sub.2 Me                                                                         --O--                                                                              ═O                                                                            9 #STR59##                                           40     H 2-Cl                                                                              5-CONH.sub.2                                                                          --O--                                                                              ═O                                                                            4 #STR60##                                           __________________________________________________________________________

                                      TABLE 5                                      __________________________________________________________________________     1 #STR61##                                                                     Compound No.                                                                          R.sup.1                                                                          R.sup.2                                                                           R.sup.3                                                                              Y.sup.1                                                                            W   NR.sup.4 R.sup.5                                     __________________________________________________________________________     41     H 2-Cl                                                                              5-CONH.sub.2                                                                         --O--                                                                              ═O                                                                             9 #STR62##                                           42     H 2-Cl                                                                              5-CONHMe                                                                             --O--                                                                              ═O                                                                             4 #STR63##                                           43     H 2-Cl                                                                              5-CONHMe                                                                             --O--                                                                              ═O                                                                             9 #STR64##                                           44     H 2-Cl                                                                              5-CONMe.sub.2                                                                        --O--                                                                              ═O                                                                             4 #STR65##                                           45     H 2-Cl                                                                              5-CONMe.sub.2                                                                        --O--                                                                              ═O                                                                             9 #STR66##                                           __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________     1 #STR67##                                                                     Compound No.                                                                          R.sup.1                                                                          R.sup.2                                                                           R.sup.3 Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                    __________________________________________________________________________     46     H 2-Cl                                                                              3-NH.sub.2                                                                             --O--                                                                              ═O                                                                            4 #STR68##                                          47     H 2-Cl                                                                              3-NH.sub.2                                                                             --O--                                                                              ═O                                                                            9 #STR69##                                          48     H 2-Cl                                                                              3-NHMe  --O--                                                                              ═O                                                                            4 #STR70##                                          49     H 2-Cl                                                                              3-NHMe  --O--                                                                              ═O                                                                            9 #STR71##                                          50     H 2-Cl                                                                              3-NMe.sub.2                                                                            --O--                                                                              ═O                                                                            4 #STR72##                                          51     H 2-Cl                                                                              3-NMe.sub.2                                                                            --O--                                                                              ═O                                                                            9 #STR73##                                          52     H 2-Cl                                                                              3-CH.sub.2 OCH.sub.2 OMe                                                               --O--                                                                              ═O                                                                            4 #STR74##                                          53     H 2-Cl                                                                              3-CH.sub.2 OCH.sub.2 OMe                                                               --O--                                                                              ═O                                                                            9 #STR75##                                          54     H 2-Cl                                                                              3-CH.sub.2 OSiMe.sub.2                                                                 --O--                                                                              ═O                                                                            4 #STR76##                                          __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________     1 #STR77##                                                                     Compound                                                                       No.   R.sup.1                                                                          R.sup.2                                                                           R.sup.3                                                                               Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                      __________________________________________________________________________     55    H 2-Cl                                                                              3-CH.sub.2 OSiMe.sub.3                                                                --O--                                                                              ═O                                                                            2 #STR78##                                            56    H 2-Cl                                                                              3-CH.sub.2 OH                                                                         --O--                                                                              ═O                                                                            3 #STR79##                                            57    H 2-Cl                                                                              3-CH.sub.2 OH                                                                         --O--                                                                              ═O                                                                            2 #STR80##                                            58    H 2-Cl                                                                              3-CN   --O--                                                                              ═O                                                                            3 #STR81##                                            59    H 2-Cl                                                                              3-CN   --O--                                                                              ═O                                                                            2 #STR82##                                            60    H 2-Cl                                                                              3-CO.sub.2 H                                                                          --O--                                                                              ═O                                                                            3 #STR83##                                            61    H 2-Cl                                                                              3-CO.sub.2 H                                                                          --O--                                                                              ═O                                                                            2 #STR84##                                            62    H 2-Cl                                                                              3-CO.sub.2 Me                                                                         --O--                                                                              ═O                                                                            3 #STR85##                                            63    H 2-Cl                                                                              3-CO.sub.2 Me                                                                         --O--                                                                              ═O                                                                            2 #STR86##                                            64    H 2-Cl                                                                              3-CONH.sub.2                                                                          --O--                                                                              ═O                                                                            3 #STR87##                                            __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________     1 #STR88##                                                                     Compound                                                                       No.   R.sup.1                                                                          R.sup.2                                                                           R.sup.3                                                                               Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                      __________________________________________________________________________     65    H 2-Cl                                                                              3-CONH.sub.2                                                                          --O--                                                                              ═O                                                                            2 #STR89##                                            66    H 2-Cl                                                                              3-CONHMe                                                                              --O--                                                                              ═O                                                                            3 #STR90##                                            67    H 2-Cl                                                                              3-CONHMe                                                                              --O--                                                                              ═O                                                                            2 #STR91##                                            68    H 2-Cl                                                                              3-CONMe.sub.2                                                                         --O--                                                                              ═O                                                                            3 #STR92##                                            69    H 2-Cl                                                                              3-CONMe.sub.2                                                                         --O--                                                                              ═O                                                                            2 #STR93##                                            __________________________________________________________________________

                                      TABLE 9                                      __________________________________________________________________________     1 #STR94##                                                                     Compound                                                                       No.   R.sup.1                                                                          R.sup.2                                                                           R.sup.3                                                                               Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                      __________________________________________________________________________     70    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --O--                                                                              ═O                                                                            4 #STR95##                                            71    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --O--                                                                              ═O                                                                            3 #STR96##                                            72    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --O--                                                                              ═O                                                                            2 #STR97##                                            73    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --O--                                                                              ═S                                                                            3 #STR98##                                            74    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --O--                                                                              ═S                                                                            2 #STR99##                                            75    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --S--                                                                              ═O                                                                            3 #STR100##                                           76    2-Cl                                                                             3-NH.sub.2                                                                        6-Cl   --S--                                                                              ═O                                                                            2 #STR101##                                           77    2-Cl                                                                             3-NHMe                                                                            6-Cl   --O--                                                                              ═O                                                                            3 #STR102##                                           78    2-Cl                                                                             3-NHMe                                                                            6-Cl   --O--                                                                              ═O                                                                            2 #STR103##                                           79    2-Cl                                                                             3-NMe.sub.2                                                                       6-Cl   --O--                                                                              ═O                                                                            3 #STR104##                                           __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________     1 #STR105##                                                                    Compound No.                                                                          R.sup.1                                                                           R.sup.2 R.sup.3                                                                           Y.sup.1                                                                            W  NR.sup.4 R.sup.5                                   __________________________________________________________________________     80     2-Cl                                                                              3-NMe.sub.2                                                                            6-Cl                                                                              --O--                                                                              ═O                                                                            9 #STR106##                                        81     2-Cl                                                                              3-CH.sub.2 OCH.sub.2 OMe                                                               6-Cl                                                                              --O--                                                                              ═O                                                                            4 #STR107##                                        82     2-Cl                                                                              3-CH.sub.2 OCH.sub.2 OMe                                                               6-Cl                                                                              --O--                                                                              ═O                                                                            9 #STR108##                                        83     2-Cl                                                                              3-CH.sub.2 OSiMe.sub.3                                                                 6-Cl                                                                              --O--                                                                              ═O                                                                            4 #STR109##                                        84     2-Cl                                                                              3-CH.sub.2 OSiMe.sub.3                                                                 6-Cl                                                                              --O--                                                                              ═O                                                                            9 #STR110##                                        85     2-Cl                                                                              3-CH.sub.2 OH                                                                          6-Cl                                                                              --O--                                                                              ═O                                                                            4 #STR111##                                        86     2-Cl                                                                              3-CH.sub.2 OH                                                                          6-Cl                                                                              --O--                                                                              ═O                                                                            9 #STR112##                                        87     2-Cl                                                                              3-CN    6-Cl                                                                              --O--                                                                              ═O                                                                            4 #STR113##                                        88     2-Cl                                                                              3-CN    6-Cl                                                                              --O--                                                                              ═O                                                                            9 #STR114##                                        89     2-Cl                                                                              3-CO.sub.2 H                                                                           6-Cl                                                                              --O--                                                                              ═O                                                                            4 #STR115##                                        __________________________________________________________________________

                                      TABLE 11                                     __________________________________________________________________________     1 #STR116##                                                                    Compound No.                                                                          R.sup.1                                                                           R.sup.2                                                                              R.sup.3                                                                           Y.sup.1                                                                            W   NR.sup.4 R.sup.5                                    __________________________________________________________________________     90     2-Cl                                                                              3-CO.sub.2 H                                                                         6-Cl                                                                              --O--                                                                              ═O                                                                             9 #STR117##                                         91     2-Cl                                                                              3-CO.sub.2 Me                                                                        6-Cl                                                                              --O--                                                                              ═O                                                                             4 #STR118##                                         92     2-Cl                                                                              3-CO.sub.2 Me                                                                        6-Cl                                                                              --O--                                                                              ═O                                                                             9 #STR119##                                         93     2-Cl                                                                              3-CONH.sub.2                                                                         6-Cl                                                                              --O--                                                                              ═O                                                                             4 #STR120##                                         94     2-Cl                                                                              3-CONH.sub.2                                                                         6-Cl                                                                              --O--                                                                              ═O                                                                             9 #STR121##                                         95     2-Cl                                                                              3-CONHMe                                                                             6-Cl                                                                              --O--                                                                              ═O                                                                             4 #STR122##                                         96     2-Cl                                                                              3-CONHMe                                                                             6-Cl                                                                              --O--                                                                              ═O                                                                             9 #STR123##                                         97     2-Cl                                                                              3-CONMe.sub.2                                                                        6-Cl                                                                              --O--                                                                              ═O                                                                             4 #STR124##                                         98     2-Cl                                                                              3-CONMe.sub.2                                                                        6-Cl                                                                              --O--                                                                              ═O                                                                             9 #STR125##                                         __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________     1 #STR126##                                                                    Compound                                                                       No.    R.sup.1                                                                            R.sup.2  R.sup.3                                                                           Y.sup.1                                                                             W   NR.sup.4 R.sup.5                               __________________________________________________________________________     99     2-Cl                                                                               3-NH.sub.2                                                                              6-F                                                                               --O--                                                                               ═O                                                                             3 #STR127##                                    100    2-Cl                                                                               3-NH.sub.2                                                                              6-F                                                                               --O--                                                                               ═O                                                                             2 #STR128##                                    101    2-Cl                                                                               3-NHMe   6-F                                                                               --O--                                                                               ═O                                                                             3 #STR129##                                    102    2-Cl                                                                               3-NHMe   6-F                                                                               --O--                                                                               ═O                                                                             2 #STR130##                                    103    2-Cl                                                                               3-NMe.sub.2                                                                             6-F                                                                               --O--                                                                               ═O                                                                             3 #STR131##                                    104    2-Cl                                                                               3-NMe.sub.2                                                                             6-F                                                                               --O--                                                                               ═O                                                                             2 #STR132##                                    105    2-Cl                                                                               3-CH.sub.2 OCH.sub.2 OMe                                                                6-F                                                                               --O--                                                                               ═O                                                                             3 #STR133##                                    106    2-Cl                                                                               3-CH.sub.2 OCH.sub.2 OMe                                                                6-F                                                                               --O--                                                                               ═O                                                                             2 #STR134##                                    107    2-Cl                                                                               3-CH.sub.2 OSiMe.sub.3                                                                  6-F                                                                               --O--                                                                               ═O                                                                             3 #STR135##                                    108    2-Cl                                                                               3-CH.sub.2 OSiMe.sub.3                                                                  6-F                                                                               --O--                                                                               ═O                                                                             2 #STR136##                                    __________________________________________________________________________

                  TABLE 13                                                         ______________________________________                                         1 #STR137##                                                                    Com-                                                                           pound                                                                          No.    R.sup.1                                                                               R.sup.2  R.sup.3                                                                            Y.sup.1                                                                              W    NR.sup.4 R.sup.5                         ______________________________________                                         109    2-Cl   3-CH.sub.2 OH                                                                           6-F --O-- ═O                                                                              7 #STR138##                              110    2-Cl   3-CH.sub.2 OH                                                                           6-F --O-- ═O                                                                              8 #STR139##                              111    2-Cl   3-CN     6-F --O-- ═O                                                                              7 #STR140##                              112    2-Cl   3-CN     6-F --O-- ═O                                                                              8 #STR141##                              113    2-Cl   3-CO.sub.2 H                                                                            6-F --O-- ═O                                                                              7 #STR142##                              114    2-Cl   3-CO.sub.2 H                                                                            6-F --O-- ═O                                                                              8 #STR143##                              115    2-Cl   3-CO.sub.2 Me                                                                           6-F --O-- ═O                                                                              7 #STR144##                              116    2-Cl   3-CO.sub.2 Me                                                                           6-F --O-- ═O                                                                              8 #STR145##                              117    2-Cl   3-CONH.sub.2                                                                            6-F --O-- ═O                                                                              7 #STR146##                              118    2-Cl   3-CONH.sub.2                                                                            6-F --O-- ═O                                                                              8 #STR147##                              ______________________________________                                    

                  TABLE 14                                                         ______________________________________                                         1 #STR148##                                                                    Com-                                                                           pound                                                                          No.   R.sup.1                                                                               R.sup.2   R.sup.3                                                                            Y.sup.1                                                                              W    NR.sup.4 R.sup.5                         ______________________________________                                         119   2-Cl   3-CONHMe  6-F --O-- ═O                                                                              7 #STR149##                              120   2-Cl   3-CONHMe  6-F --O-- ═O                                                                              8 #STR150##                              121   2-Cl   3-CONMe.sub.2                                                                            6-F --O-- ═O                                                                              7 #STR151##                              122   2-Cl   3-CONMe.sub.2                                                                            6-F --O-- ═O                                                                              8 #STR152##                              ______________________________________                                    

                  TABLE 15                                                         ______________________________________                                         2 #STR153##                                                                    Compound                                                                       No.     R.sup.11 R.sup.12                                                                              R.sup.13                                                                              R.sup.14                                                                            NR.sup.9 N.sup.10                          ______________________________________                                         123     H        H      H      H                                                                                   9 #STR154##                                124     H        H      2-Cl   H                                                                                   9 #STR155##                                125     H        H      2-Me   H                                                                                   9 #STR156##                                126     H        H      2-MeO  H                                                                                   9 #STR157##                                127     H        2-Cl   6-Cl   H                                                                                   9 #STR158##                                128     H        2-Cl   6-Cl   H                                                                                   0 #STR159##                                129     H        2-Cl   6-Cl   H                                                                                   1 #STR160##                                130     H        2-Cl   6-Cl   H                                                                                   2 #STR161##                                131     H        2-Cl   6-Cl   Me                                                                                  2 #STR162##                                132     H        2-Cl   6-Cl   Ph                                                                                  2 #STR163##                                ______________________________________                                    

                  TABLE 16                                                         ______________________________________                                         3 #STR164##                                                                    Compound                                                                       No.      R.sup.11                                                                              R.sup.12                                                                              R.sup.13                                                                             Y.sup.1                                                                               NR.sup.9 R.sup.10                          ______________________________________                                         133      H      H      H     --O--                                                                                 9 #STR165##                                134      H      H      2-Cl  --O--                                                                                 9 #STR166##                                135      H      H      2-Me  --O--                                                                                 9 #STR167##                                136      H      H      2-MeO --O--                                                                                 9 #STR168##                                137      H      H      2-NO.sub.2                                                                           --O--                                                                                 9 #STR169##                                138      H      2-Cl   6-Cl  --O--                                                                                 9 #STR170##                                139      H      2-Cl   6-Cl  --O--                                                                                 0 #STR171##                                140      H      2-Cl   6-Cl  --O--                                                                                 2 #STR172##                                141      H      2-Cl   6-Cl  --S--                                                                                 9 #STR173##                                142      H      2-Cl   6-Cl  --S--                                                                                 7 #STR174##                                ______________________________________                                    

                  TABLE 17                                                         ______________________________________                                         4 #STR175##                                                                    Compound No.                                                                            R.sup.11                                                                              R.sup.12                                                                               R.sup.13                                                                            Y.sup.1                                                                               3 #STR176##                                ______________________________________                                         143      H      H       H    --O--                                                                                 4 #STR177##                                144      H      H       2-Cl --O--                                                                                 4 #STR178##                                145      H      2-Cl    6-Cl --O--                                                                                 4 #STR179##                                146      H      2-Cl    6-Cl --O--                                                                                 5 #STR180##                                147      H      2-Cl    6-Cl --O--                                                                                 6 #STR181##                                148      H      2-Cl    6-Cl --O--                                                                                 7 #STR182##                                149      H      2-Cl    6-Cl --O--                                                                                 8 #STR183##                                150      H      2-Cl    6-Cl --O--                                                                                 9 #STR184##                                151      H      2-Cl    6-Cl --S--                                                                                 4 #STR185##                                152      H      2-Cl    6-Cl --S--                                                                                 8 #STR186##                                ______________________________________                                    

                  TABLE 18                                                         ______________________________________                                         5 #STR187##                                                                    Compound                                                                       No.     R.sup.11                                                                              R.sup.12                                                                              R.sup.13                                                                            Y.sup.1                                                                              n.sup.2                                                                             R.sup.17                                 ______________________________________                                         153     H      H      H    --O-- 1    --SMe                                    154     H      H      2-Cl --O-- 1    --SMe                                    155     H      2-Cl   6-Cl --O-- 1    --SMe                                    156     H      2-Cl   6-Cl --O-- 1    --OMe                                    157     H      2-Cl   6-Cl --O-- 1    --OCH.sub.2 CH.sub.2 OMe                 158     H      2-Cl   6-Cl --O-- 2    --SMe                                    159     H      2-Cl   6-Cl --O-- 2    --OMe                                    160     H      2-Cl   6-Cl --O-- 2    --Br                                     161     H      2-Cl   6-Cl --O-- 2                                                                                   7 #STR188##                              162     H      2-Cl   6-Cl --S-- 1    --OCH.sub.2 CH.sub.2 OMe                 ______________________________________                                    

                  TABLE 19                                                         ______________________________________                                         6 #STR189##                                                                    Compound                                                                       No.          R.sup.11 R.sup.12 R.sup.13                                                                               n.sup.3                                 ______________________________________                                         163          H        H        2-Cl    0                                       164          H        H        3-Cl    0                                       165          H        H        4-Cl    0                                       166          H        H        2-Me    0                                       167          H        H        3-Me    0                                       168          H        H        4-Me    0                                       169          H        H        2-F     0                                       170          H        H        3-F     0                                       171          H        H        4-F     0                                       172          H        H        2-CF.sub.3                                                                             0                                       ______________________________________                                    

                  TABLE 20                                                         ______________________________________                                         1 #STR190##                                                                    Compound                                                                       No.         R.sup.11 R.sup.12 R.sup.13                                                                             n.sup.3                                    ______________________________________                                         173         H        H        3-CF.sub.3                                                                           0                                          174         H        H        4-CF.sub.3                                                                           0                                          175         H        H        2-NO.sub.2                                                                           0                                          176         H        H        3-NO.sub.2                                                                           0                                          177         H        H        4-NO.sub.2                                                                           0                                          178         H        H        2-MeO 0                                          179         H        H        3-MeO 0                                          180         H        H        4-MeO 0                                          181         H        H        2-OH  0                                          182         H        H        3-OH  0                                          ______________________________________                                    

                  TABLE 21                                                         ______________________________________                                         1 #STR191##                                                                    Compound                                                                       No.          R.sup.11 R.sup.12 R.sup.13                                                                             n.sup.3                                   ______________________________________                                         183          H        H        4-OH  0                                         184          H        2-Cl     6-Cl  0                                         185          H        H        2-Cl  1                                         186          H        H        2-Me  1                                         187          H        H        2-F   1                                         188          H        H        2-CF.sub.3                                                                           1                                         189          H        H        2-NO.sub.2                                                                           1                                         190          H        H        2-MeO 1                                         191          H        H        2-OH  1                                         192          H        2-Cl     6-Cl  1                                         ______________________________________                                    

                                      TABLE 22                                     __________________________________________________________________________     2 #STR192##                                                                    Com-                                                                           pound                                                                          No.    R.sup.11                                                                          R.sup.12                                                                           R.sup.13                                                                          n.sup.3                                                                           W  NR.sup.4 R.sup.5                                        __________________________________________________________________________     193    H  H   H  0  ═O                                                                            4 #STR193##                                             194    H  H   H  0  ═O                                                                            5 #STR194##                                             195    H  H   2-Cl                                                                              0  ═O                                                                            6 #STR195##                                             196    H  H   2-Cl                                                                              0  ═S                                                                            6 #STR196##                                             197    H  H   2-Cl                                                                              0  ═O                                                                            7 #STR197##                                             198    H  H   2-Cl                                                                              0  ═O                                                                            8 #STR198##                                             199    H  2-Cl                                                                               6-Cl                                                                              0  ═O                                                                            6 #STR199##                                             200    H  2-Cl                                                                               6-Cl                                                                              0  ═O                                                                            7 #STR200##                                             201    H  H   H  1  ═O                                                                            4 #STR201##                                             202    H  H   2-Cl                                                                              1  ═O                                                                            6 #STR202##                                             __________________________________________________________________________

                  TABLE 23                                                         ______________________________________                                         2 #STR203##                                                                    Compound                                                                       No.      R.sup.11                                                                              R.sup.12                                                                              R.sup.13                                                                            n.sup.3                                                                            W    NR.sup.4 R.sup.5                          ______________________________________                                         203      H      H      2-Cl 1   ═S                                                                              6 #STR204##                               204      H      H      2-Cl 1   ═O                                                                              7 #STR205##                               205      H      2-Cl   6-Cl 1   ═O                                                                              6 #STR206##                               206      H      2-Cl   6-Cl 1   ═O                                                                              7 #STR207##                               ______________________________________                                    

                  TABLE 24                                                         ______________________________________                                         3 #STR208##                                                                    Com-                                                                           pound                                                                          No.    R.sup.11                                                                              R.sup.12                                                                              R.sup.13                                                                             Y.sup.1                                                                              W    NR.sup.14 R.sup.18                       ______________________________________                                         207    H      H      H     --O-- ═O                                                                              7 #STR209##                              208    H      H      2-Cl  --O-- ═O                                                                              7 #STR210##                              209    H      H      3-Cl  --O-- ═O                                                                              7 #STR211##                              210    H      H      2-Me  --O-- ═O                                                                              7 #STR212##                              211    H      H      3-CF.sub.3                                                                           --O-- ═O                                                                              7 #STR213##                              212    H      H      2-OMe --O-- ═O                                                                              7 #STR214##                              213    H      H      2-OH  --O-- ═O                                                                              7 #STR215##                              214    H      H      2-NO.sub.2                                                                           --O-- ═O                                                                              7 #STR216##                              215    H      2-Cl   6-F   --O-- ═O                                                                              7 #STR217##                              216    H      2-Cl   5-NO.sub.2                                                                           --O-- ═O                                                                              7 #STR218##                              ______________________________________                                    

                                      TABLE 25                                     __________________________________________________________________________     3 #STR219##                                                                    Compound                                                                       No.    R.sup.11                                                                          R.sup.12                                                                           R.sup.13                                                                           Y.sup.1                                                                             W  NR.sup.14 R.sup.18                                   __________________________________________________________________________     217    H  2-Cl                                                                               5-OH                                                                               --O--                                                                               ═O                                                                            7 #STR220##                                          218    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            9 #STR221##                                          219    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            7 #STR222##                                          220    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            0 #STR223##                                          221    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            1 #STR224##                                          222    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            2 #STR225##                                          223    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            3 #STR226##                                          224    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═O                                                                            4 #STR227##                                          225    H  2-Cl                                                                               6-Cl                                                                               --O--                                                                               ═S                                                                            7 #STR228##                                          226    H  2-Cl                                                                               6-Cl                                                                               --S--                                                                               ═O                                                                            7 #STR229##                                          __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________     3 #STR230##                                                                    Com-                                                                           pound                                                                          No.    R.sup.11                                                                           R.sup.12                                                                           R.sup.13                                                                            Y.sup.1                                                                            W  NR.sup.14 R.sup.18                                  __________________________________________________________________________     227    H   2-Cl                                                                               6-Cl --S--                                                                              ═S                                                                            7 #STR231##                                         228    2-Cl                                                                               3-Cl                                                                               6-Cl --O--                                                                              ═O                                                                            7 #STR232##                                         229    2-Cl                                                                               3-OH                                                                               6-Cl --O--                                                                              ═O                                                                            7 #STR233##                                         230    2-Cl                                                                               3-NO.sub.2                                                                         6-Cl --O--                                                                              ═O                                                                            7 #STR234##                                         231    2-Cl                                                                               3-NO.sub.2                                                                         6-F  --O--                                                                              ═O                                                                            7 #STR235##                                         __________________________________________________________________________

The arylthiadiazole derivatives represented by. General Formulas I! and II!, and salts thereof have useful pharmaceutical properties, in particular, antiviral effects. The medical composition containing the above compound is useful for curative treatment of virus-infected patients, or preliminary treatment of persons who may possibly be infected with a virus.

The DNA type viruses which will be killed by the virucide of the present invention include Herpes simplex virus type 1, Herpes simplex virus type 2, Human cytomegalovirus, Epstein-Barr virus, Varicella zoster virus, and Human herpes virus 6 of Herpesviridae family; Human adenovirus of Adenoviridae family; Hepatitis B virus of Hepadnaviridae family; Human papilloma virus of Papovaviridae family, and the like.

The RNA type viruses which will be killed by the virucide of the present invention include Rubella virus, Japanese encephalitis virus, and Hepatitis C virus of Togaviridae family; Measles virus, Respiratory syncytial virus, and Humps virus of Paramyxoviridae family; Influenza virus of Orthomyxoviridae family; Rabies virus of Rhabdoviridae family; Human T-lymphotropic virus, and Human immunodeficiency virus of Retroviridae family; Human polio virus, and Hepatitis A virus of Picornaviridae family; and the like. In particular, the virucide of the present invention is effective against Human immunodeficiency virus (HIV).

The arylthiadiazole derivative represented by General Formula I! or II!, or the salt thereof as the virucide can be dosed by oral administration, parenteral administration (hypodermic, intravenous, intramuscular, and sternum injection), or intrarectal administration. For the administration, the arylthiadiazole derivative represented by General Formula I! or II!, or the salt thereof is dosed in a state of a formulation prepared by mixing with a suitable carrier. The formulation includes tablets, granules, fine grains, powders, capsules, injection, ophthalmic solutions, ophthalmic ointments, and suppositories. The active ingredient is contained in the formulation at a content of from about 0.01 to 99.99%. The dosage depends on the kind of the objective virus, the symptom, the patient's age, and the dosing method, and is usually in the range of from about 0.01 to 500 mg/kg/day in terms of the active ingredient.

The present invention is described specifically by reference to examples without limiting the invention thereto.

EXAMPLE 1

Production of N,N-dimethyl 3-(3-amino-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 70)

In 10 mL of ethanol, was dissolved 100 mg of N,N-dimethyl 3-(2,6-dichloro-3-nitrophenyl)-1,2,5-thiadiazol-4-yl! carbamate. To this solution, 10 mg of platinum oxide, and 0.1 mL of acetic acid were added, and the mixture was stirred in a hydrogen atmosphere at room temperature. After stirring for 2 hours, the liquid reaction mixture was filtered through Celite. The filtrate is concentrated, and purified by preparative silica gel thin layer chromatography to obtain 80 mg of N,N-dimethyl 3-(3-amino-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Melting Point: 120-123° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 2.90 (s, 3H), 2.95 (s, 3H), 4.3 (br s, 2H), 6.80 (d, J=9 Hz, 1H), 7.16 (d, J=9 Hz, 1H) IR (KBr, cm⁻¹): 3480, 3460, 3390, 3350, 1740, 1620, 1460, 1370, 1325, 1220, 1150, 815

Typical compounds were prepared in the same manner as in Example 1. The properties are shown in Examples 2-5.

EXAMPLE 2

N,N-Dimethyl 3-(5-amino-2-chlorophenyl)-1,2,5-thiadiazol-4-yl! CARBAMATE (Compound 21)

Melting Point: 121-124° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 2.93 (s, 3H), 3.03 (s, 3H), 3.4 (br s, 2H), 6.70 (dd, J=3, 8.5 Hz, 1H), 6.76 (d, J=3 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H) IR (KBr, cm⁻¹) 3440, 3340, 1730, 1595, 1455, 1375, 1160, 810

EXAMPLE 3

N-Methyl-N-propyl 3-(3-amino-2-chloro-6-fluorophenyl)-1,2,5-thiadiazole-4-yl! carbamate (Compound 99)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.80 (t, J=7.5 Hz), 0.81 (t, J=7.5 Hz), 3H!, 1.48 (sextet, J=7.5 Hz), 1.50 (sextet, J=7.5 Hz), 2H!, 2.91 (s), 2.95 (s), 3H!, 3.20 (t, J=7.5 Hz), 3.25 (t, J=7.5 Hz), 2H!, 3.9 (br s, 2H), 6.7-7.1 (m, 2H) IR (neat, cm⁻¹): 3470, 3360, 1735, 1475, 1385, 1210, 1150

EXAMPLE 4

N-Methyl-N-propyl 3-(3-amino-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 71)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.75 (t, J=7.5 Hz), 0.76 (t, J=7.5 Hz), 3H!, 1.44 (sextet, J=7.5 Hz), 1.45 (sextet, J=7.5 Hz), 2H!, 2.89 (s), 2.90 (s), 3H!, 3.16 (t, J=7.5 Hz), 3.21 (t, J=7.5 Hz), 2H!, 4.26 (br s, 2H), 6.78 (d, J=9 Hz), 6.79 (d, J=9 Hz), 1H!, 7.14 (d, J=9 Hz, 1H) IR (neat, cm⁻¹): 3480, 3360, 1740, 1620, 1460, 1380, 1220, 1150

EXAMPLE 5

N-Methyl-N-propyl 3-(5-amino-2-chlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 22)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.81 (t, J=7.5 Hz), 0.83 (t, J=7.5 Hz), 3H!, 1.50 (sextet, J=7.5 Hz), 1.53 (sextet, J=7.5 Hz), 2H!, 2.91 (s), 2.99 (s), 3H!, 3.20 (t, J=7.5 Hz), 3.29 (t, J=7.5 Hz), 2H!, 3.70 (br s, 2H), 6.68 (dd, J=3, 8.5 Hz), 6.74 (d, J=3 Hz), 6.75 (d, J=3 Hz), 1H!, 7.20(d, J=8.5 Hz, 1H) IR (neat, cm⁻¹): 3460, 3360, 1735, 1460, 1390, 1305, 1210, 1150

EXAMPLE 6

Production of N¹ -diethyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl!formamidine (Compound 130)

0.2 Gram of N,N-diethylformamide was dissolved in 1 mL of benzene. Thereto 0.15 g of phosphorus oxychloride was added. The mixture was stirred at room temperature for 12 hours. To this reaction mixture, 0.12 g of 3-(2,6-dichlorophenyl)-4-amino-1,2,5-thiadiazole was added, and the mixture was refluxed by heating for one hour. Then the mixture was left standing to allow it to cool to room temperature. The reaction mixture was poured into water, and was extracted with ether. The ether layer was washed by 10% sodium hydrodgencarbonate twice, and by water twice, dried over anhydrous magnesium sulfate, and was concentrated. The concentrate was purified by silica gel column chromatography to obtain 0.15 g of N¹ -diethyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl!formamidine.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 1.00 (t, J=7 Hz, 3H,), 1.17 (t, J=7 Hz, 3H), 3.28 (q, J=7 Hz), 3.30 (q, J=7 Hz), 4H!, 7.2-7.4 (m, 3H), 8.32 (s, 1H) IR (neat, cm⁻¹): 1610, 1485, 1460, 1425, 1395, 1360, 1125, 795

Typical compounds were prepared in the same manner as in Example 6. The properties are shown in Examples 7-10.

EXAMPLE 7

N¹ -Dimethyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! formamidine (Compound 127)

Melting Point: 100-103° C.

⁻¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 2.88 (s, 3H), 3.04 (s, 3H), 7.2-7.4 (m, 3H), 8,35 (s, 1H) IR (KBr, cm⁻¹): 1630, 1505, 1470, 1430, 1390, 1120, 1105, 795

EXAMPLE 8

N¹ -methyl-N¹ -propyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl!formamidine (Compound 128)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.73 (t, J=7 Hz, 1H,), 0.88 (t, J=7 Hz, 2H), 1.4-1.7 (m, 2H), 2.86 (s, 2H), 3.02 (s, 1H), 3.25 (q, J=7 Hz, 2H), 7.2-7.4 (m, 3H), 8.35 (s, 1H) IR (neat, cm⁻¹): 1615, 1490, 1465, 1430, 1390, 1125, 795

EXAMPLE 9

N¹ -diethyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl!acetamidine (Compound 131)

Melting point: 39-40° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 0.85 (br s, 3H), 1.11 (br s, 3H), 2.20 (s, 3H), 3.29 (q, J=7 Hz, 4H), 7.2-7.4 (m, 3H) IR (KBr, cm⁻¹): 1560, 1550, 1425, 1390, 1355, 790

EXAMPLE 10

N¹ -diethyl-N² - 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl!benzamidine (Compound 132)

Melting point: 54-55° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.99 (t, J=7 Hz, 6H), 3.03 (br, q, J=7 Hz, 2H), 3.49 (br q, J=7 Hz, 2H), 7.1-7.5 (m, 8H) IR (KBr, cm⁻¹): 1565, 1555, 1425, 1390, 1360, 790, 780

EXAMPLE 11

Production of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 163)

In 1,3-dimethyl-2-imidazolidinone, were stirred 280 mg of 3-bromo-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 180 mg of copper cyanide at 150° C. for 12 hours. After spontaneous cooling, the reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The diethyl layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole. The obtained 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole (120 mg) was heated with 6 mL of 5% sodium hydroxide solution and 2 mL of ethanol, and refluxed for one hour. After spontaneous cooling, the reaction mixture was poured into a dilute hydrochloric acid solution, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 100 mg of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid.

Melting point: 112-114° C.

IR (KBr, cm⁻¹): 3600-2400, 1705, 1270, 1240, 1165, 750 Elemental analysis (%) as C₉ H₅ ClN₂ O₂ S Calculated: C: 44.92, H: 2.09, N: 11.64 Found: C: 44.64, H: 2.19, N: 11.52

Typical compounds were prepared in the same manner as in Example 11. The properties are shown in Examples 12-22.

EXAMPLE 12

4-(3-Chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 164)

Melting point: 163-165° C.

IR (KBr, cm⁻¹): 3200-2400, 1700, 1460, 1270, 1160, 770 Elemental analysis (%) as C₉ H₅ ClN₂ O₂ S Calculated: C: 44.92, H: 2.09, N: 11.64 Found: C: 44.94, H: 2.38, N: 11.84

EXAMPLE 13

4-(4-Chlororhenyl) -1,2,5-thiadiazole -3-carboxylic acid (Comound 165)

Melting point: 157-158° C.

IR (KBr, cm⁻¹): 3300-2400, 1700, 1465, 1440, 1295, 1160, 1090, 820 Elemental analysis (%) as C₉ H₅ ClN₂ O₂ S Calculated: C: 44.92, H: 2.09, N: 11.64 Found: C: 44.68, H: 2.32, N: 11.51

EXAMPLE 14

4-(2-Tolyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 166)

Melting point: 119-121° C.

IR (KBr, cm⁻¹) 3300-2400, 1700, 1460, 1450, 1260, 1155, 850, 765, 745 Elemental analysis (%) as C₁₀ H₈ N₂ O₂ S Calculated: C: 54.53, H: 3.66, N: 12.72 Found: C: 54.29, H: 3.89, N: 12.71

EXAMPLE 15

4-(3-Tolyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 167)

Melting point: 118-120° C.

IR (KBr, cm⁻¹): 3200-2400, 1700, 1460, 1450, 1280, 1140, 770 Elemental analysis (%) as C₁₀ H₈ N₂ O₂ S Calculated: C: 54.53, H: 3.66, N: 12.72 Found: C: 54.42, H: 3.56, N: 12.71

EXAMPLE 16

4-(4-Tolyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 168)

Melting point: 128-130° C.

IR (KBr, cm⁻¹): 3300-2400, 1700, 1455, 1435, 1295, 1150 Elemental analysis (%) as C₁₀ H₈ N₂ O₂ S Calculated: C: 54.53, H: 3.66, N: 12.72 Found: C: 54.33, H: 3.62, N: 12.59

EXAMPLE 17

4-(3-Fluorophenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 170)

Melting point: 153-156° C.

IR (KBr, cm⁻¹): 3200-2400, 1700, 1460, 1210, 870, 855, 770 Elemental analysis (%) as C₉ H₅ FN₂ O₂ S Calculated: C: 48.21, H: 2.25, N: 12.49 Found: C: 48.04, H: 2.54, N: 12.69

EXAMPLE 18

4-(4-Fluorophenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 171)

Melting point: 165-166° C.

IR (KBr, cm⁻¹): 3300-2400, 1700, 1460, 1440, 1220, 1160, 830 Elemental analysis (%) as C₉ H₅ FN₂ O₂ S Calculated: C: 48.21, H: 2.25, N: 12.49 Found: C: 47.97, H: 2.47, N: 12.48

EXAMPLE 19

4-(3-Trifluoromethylphenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 173)

Melting point: 122-124° C.

IR (KBr, cm⁻¹) 3200-2400, 1700, 1325, 1295, 1155, 1110 Elemental analysis (%) as C₁₀ H₅ F₃ N₂ O₂ S Calculated: C: 43.80, H: 1.84, N: 10.22 Found: C: 43.63, H: 2.13, N: 10.41

EXAMPLE 20

4-(4-Trifluoromethylphenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 174)

Melting point: 135-137° C.

IR (KBr, cm⁻¹): 3200-2400, 1700, 1460, 1320, 1160, 1110 Elemental analysis (%) as C₁₀ H₅ F₃ N₂ O₂ S Calculated: C: 43.80, H: 1.84, N: 10.22 Found: C: 43.56, H: 2.06, N: 10.20

EXAMPLE 21

4-(3-Nitrophenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 176)

Melting point: 193-194° C.

IR (KBr, cm⁻¹): 3400-2400, 1705, 1525, 1465, 1340 Elemental analysis (%) as C₉ H₅ N₃ O₄ S Calculated: C: 43.03, H: 2.01, N: 16.73 Found: C: 42.86, H: 2.29, N: 16.92

EXAMPLE 22

4-(4-Methoxyphenyl)-1,2,5-thiadiazole-3-carboxylic acid (Compound 180)

Melting point: 118-120° C.

IR (KBr, cm⁻¹): 3200-2400, 1700, 1605, 1460, 1440, 1250, 1155 Elemental analysis (%) as C₁₀ H₈ N₂ O₃ S Calculated: C: 50.84, H: 3.41, N: 11.86 Found: C: 50.60, H: 3.64, N: 11.85

EXAMPLE 23

Production of N-methyl-N-propyl 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxamide (Compound 195)

In 1 mL of dichloromethane, was dissolved 50 mg of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid. To this solution, 70 mg of thionyl chloride was added. The solution was stirred for one hour. After spontaneous cooling to room temperature, unreacted thionyl chloride was distilled off under a reduced pressure. To the distillation residue, 1 mL of dichloromethane, 73 mg of methylpropylamine were added, and the mixture was stirred at room temperature for 6 hours. Then the reaction mixture was poured into water, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with two portions respectively of dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by preparative silica gel thin layer chromatography to obtain 50 mg of N-methyl-N-propyl 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxamide.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 0.85 (t, J=7.5 Hz), 0.88 (t, J=7.5 Hz), 3H!, 1.5-1.8 (m, 2H), 3.02 (s), 3.03 (s), 3H!, 3.21 (t, J=7.5 Hz), 3.21 (dd, J=6, 9 Hz), 1H!, 3.43 (t, J=7.5 Hz), 3.43 (dd, J=6.9 Hz), 1H!, 7.3-7.6 (m, 4H)

Typical compounds were produced in the same manner as in Example 23. The properties are shown in Examples 24-25.

EXAMPLE 24

N-Methoxy-N-methyl 4-phenyl-1,2,5-thiadiazole-3-carboxamide (Compound 194)

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm):

3.3(s, 3H), 3.5 (s, 3H), 7.2-7.9 (m, 5H) IR (KBr, cm¹): 1655, 1480, 1430, 1360, 970, 750

EXAMPLE 25

N-(4-Chloro-2-fluorophenyl) 4-(4-chlorophenyl)-1,2,5-thiadiazole-3-carboxamide (Compound 198)

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 7.0-7.8 (m, 6H), 8.3 (t, J=8 Hz, 1H), 9.1 (br s, 1H) IR (KBr, cm⁻¹): 1690, 1590, 1520, 1480, 1410, 820

EXAMPLE 26

Production of 3-(2-chlorophenyl)-1,2,5-thiadiazole-4-yl!acetic acid (Compound 185)

In N,N-dimethylformamide, 290 mg of 3-bromomethyl-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 49 mg of sodium cyanide were stirred at 90° C. for 3 hours. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole. The obtained 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole, 6 mL of 5% sodium hydroxide solution, and 2 mL of ethanol were mixed and refluxed by heating for one hour. After spontaneous cooling, the reaction mixture was poured into dilute hydrochloric acid, and was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of 3-(2-chlorophenyl)-1,2,5-thiadiazole-4-yl!acetic acid.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 3.95 (s, 2H), 7.3-7.6 (m, 3H), 8.4 (br s, 1H)

EXAMPLE 27

Production of N-methyl-N-propyl 3-(2-chlorophenyl)-1,2,5-thiadiazol-4-yl!acetamide (Compound 202)

In 1 mL of dichloromethane, was dissolved 30 mg of 3-(2-chlorophenyl)-1,2,5-thiadiazol-4-yl!acetic acid. To this solution, 60 mg of thionyl chloride was added. The mixture was stirred for one hour. After spontaneous cooling to room temperature, unreacted thionyl chloride was distilled off under a reduced pressure. To the distillation residue, 1 mL of dichloromethane, 73 mg of methylpropylamine were added, and the mixture was stirred at room temperature for 6 hours. Then the reaction mixture was poured into water, and was extracted with dichloromethane. The dichloromethane layer was washed with two portions respectively of dilute hydrochloric acid, 10% sodium hydrogencarbonate solution, and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by preparative silica gel thin layer chromatography to obtain 20 mg of N-methyl-N-propyl 3-(2-chlorophenyl)-1,2,5-thiadiazol-4-yl!acetamide.

Oily matter,

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.82 (t, J=7.5 Hz), 0.83 (t, J=7.5 Hz), 3H!, 1.3-1.6 (m, 2H), 2.86 (s), 2.97 (s), 3H!, 3.21 (t, J=7.5 Hz), 3.28 (t, J=7.5 Hz), 2H!, 3.92 (s, 2H), 7.3-7.6 (m, 4H)

EXAMPLE 28

Producition of N-(3-carboxypropyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 222)

In 10 mL of dichloromethane, were dissolved 490 mg of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, and 210 mg of bis(trichloromethyl) carbonate. Thereto, 170 mg of pyridine was added. The mixture was stirred at room temperature for 12 hours. Thereto, 340 mg of 4-(methylamino)butyric acid hydrochloride, and 570 mg of N,N-diisopropylethylamine were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and was extracted with dichloromethane. The dichloromethane layer was washed with dilute hydrochloric acid, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 510 mg of N-(3-carboxypropyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Melting point: 125-126° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 1.6-1.9 (m, 2H), 2.1-2.3 (m, 2H), 2.90 (s), 2.95 (s), 3H!, 3.26 (t, J=7.0 Hz), 3.32 (t, J=7.0 Hz), 2H!, 7.2-7.5 (m, 3H), 8.5 (br 5, 1H) IR (KBr, cm⁻¹) 3400-2400, 1740, 1700, 1430, 1380, 1295, 1230, 1180, 790

A typical compound was produced in the same manner as in Example 28. The properties of the compound are shown in Example 29.

EXAMPLE 29

N-(cyanomethyl)-N-methyl 3-(2,6-dichlorophenvl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 218)

Melting point: 106-107° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 3.02 (s), 3.09 (s), 3H!, 4.20 (s), 4.25 (s), 2H!, 7.3-7.5 (m, 3H) IR (KBr, cm⁻¹): 2250, 1745, 1430, 1380, 1280, 1230, 1205, 1135, 790, 770

EXAMPLE 30

Production of N-(2-cyanoethyl)-N-methyl 3-(2,6-dichlorophenyli-1,2,5-thiadiazol-4-yl! carbamate (Compound 219)

In 50 mL of dichloromethane, were dissolved 1.98 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, and 0.8 g of bis(trichloromethyl) carbonate. Thereto, 0.7 g of pyridine was added. The mixture was stirred at room temperature for 12 hours. Thereto, 1.51 g of N-(2-cyanoethyl)-N-methylamine was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and was extracted with dichloromethane. The dichloromethane layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 2.8 g of N-(2-cyanoethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazo1-4-yl! carbamate.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 2.46 (t, J=6.5 Hz), 2.51 (t, J=6.5 Hz), 2H!, 3.04 (s), 3.12 (s), 3H!, 3.49 (t, J=6.5 Hz), 3.59 (t, J=6.5 Hz), 2H!, 7.3-7.55 (m, 3H) IR (neat, cm⁻¹): 2250, 1740, 1430, 1380, 1230, 1195, 1125, 790

A typical compound was produced in the same manner as in Example 30. The properties of the compound are shown in Example 31.

EXAMPLE 31

N-(2-Hydroxyethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 220)

Melting point: 105-106° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 2.1 (br s, 1H), 2.97 (s), 3.02 (s), 3H!, 3.36 (t, J=5.5 Hz), 3.41 (t, J=5.5 Hz), 2H!, 3.64 (t, J=5.5 Hz, 2H), 7.3-7.5 (m, 3H) IR (KBr, cm⁻¹): 3550, 1725, 1430, 1380, 1220, 1130, 790

The properties of compounds produced in the same manner as in Example 30 are shown in Examples 32, and 33.

EXAMPLE 32

N-Methyl-N-propyl 3-(2,6-dichloro-3-cyanophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 87)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.76 (t, J=7.4 Hz), 0.80 (t, J=7.4 Hz), 3H!, 1.46 (sextet, J=7.4 Hz), 1.50 (sextet, J=7.4 Hz), 2H!, 2.89 (s), 2.96 (s), 3H!, 3.18 (t, J=7.4 Hz), 3.25 (t, J=7.4 Hz), 2H!, 7.55 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz), 7.73 (d, J=8.SHz), 1H! IR (neat, cm⁻¹): 2230, 1740, 1395, 1365, 1145

EXAMPLE 33

N-Methyl-N-propyl 3-(2,6-dichloro-3-methoxycarbonylphenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 91)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.75 (t, J=7.4 Hz), 0.77 (t, J=7.4 Hz), 3H!, 1.40 (t, J=7.4 Hz, 3H), 1.45 (sextet, J=7.4 Hz, 2H), 2.90 (s), 2.93 (s), 3H!, 3.18 (t, J=7.4 Hz), 3.22 (t, J=7.4 Hz), 2H!, 4.41 (q, J=7.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz), 7.85 (d, J=8.4 Hz), 1H! IR (neat, cm⁻¹): 1750, 1745, 1395, 1365, 1300, 1280, 1220, 1180, 1145

EXAMPLE 34

Production of N-methyl-N-propyl 3-(3-carbamoyl-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 93)

In acetonitrile, a mixture of 80 mg of 3-(3-carbamoyl-2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, 41 mg of potassium carbonate, and 41 mg of N-methyl-N-propylcarbamoyl chloride was heated and refluxed for 12 hours. After spontaneous cooling, the reaction mixture was poured into dilute hydrochloric acid, and extracted with ether. The ether layer was washed with water, and saturated aqueous sodium chloride solution successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 41 mg of N-methyl-N-propyl 3-(3-carbamoyl-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 0.78 (t, J=7.3 Hz, 3H), 1.48 (sextet, J=7.3 Hz, 2H), 2.90 (s), 2.94 (s), 3H!, 3.18 (t, J=7.3 Hz), 3.23 (t, J=7.3 Hz), 2H!, 6.21 (bs), 6.31 (bs), 2H!, 7.50 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz), 7.80 (d, J=8.4 Hz), 1H! IR (neat, cm⁻¹): 3450, 3330, 3200, 1735, 1670, 1400, 1360, 1225, 1150

The properties of a compound produced in the same manner as in Example 34 are shown in Example 35.

EXAMPLE 35

N-Methyl-N-propyl 3-(3-carboxy-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 89)

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 0.66 (t, J=7.6 Hz), 0.71 (t, J=7.6 Hz), 3H!, 1.2-1.5 (m, 2H), 2.69 (s), 2.83 (s), 3H!, 2.9-3.2 (m, 2H), 7.26 (d, J=8.1 Hz, 1H), 7.5-7.7 (m, 1H) IR (neat, cm⁻¹): 3700-3100., 1740, 1600, 1400, 1390, 1360, 1230, 1150

EXAMPLE 36

Production of N-(2-carbamoylethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 223)

In 3 mL of ethanol, was dissolved 360 mg of N-(2-cyanoethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate. Thereto, 6 mL of concentrated hydrochloric acid was added. The mixture was stirred at 30° C. for 2 hours. The reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 240 mg of N-(2-carbamoylethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Melting point: 160-161° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 2.40 (t, J=7.0 Hz), 2.44 (t, J=7.0 Hz), 2H!, 2.95 (s), 3.00 (s), 3H!, 3.52 (t, J=7.0 Hz), 3.59 (t, J=7.0 Hz), 2H!, 5.43 (br s), 5.81 (br s), 2H!, 7.3-7.5 (m, 3H) IR (KBr, cm⁻¹): 3440, 3300, 3200, 1735, 1680, 1620, 1455, 1430, 1380, 1305, 1230, 1190, 1130, 790, 780

EXAMPLE 37

Production of N-(2-carboxylethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 221)

To 360 mg of N-(2-cyanoethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate, 10 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 280 mg of N-(2-carboxyethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 2.52 (t, J=7.0 Hz), 2.53 (t, J=7.0 Hz), 2H!, 2.96 (s), 3.01 (s), 3H!, 3.49 (t, J=7.0 Hz), 3.58 (t, J=7.0 Hz), 2H!, 7.3-7.5 (m, 3H), 9.4 (br s, 1H) IR (neat, cm⁻¹): 3600-2400, 1760-1700, 1430, 1380, 1230, 1190, 1120, 790

EXAMPLE 38

Production of N- 2-(ethoxycarbonyl)ethyl!-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate (Compound 224)

In 5 mL of ethanol, was dissolved 200 mg of N-(2-carboxyethyl)-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate. Thereto, 0.2 mL of concentrated hydrochloric acid was added. The mixture was stirred at 60° C. for 6 hours. The reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with 10% sodium hydrogencarbonate solution, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 180 mg of N- 2-(ethoxycarbonyl)ethyl!-N-methyl 3-(2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl! carbamate.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 1.23 (t, J=7.0 Hz, 3H), 2.43 (t, J=7.0 Hz), 2.44 (t, J=7.0 Hz), 2H!, 2.92 (s), 2.98 (s), 3H!, 3.47 (t, J=7.0 Hz), 3.56 (t, J=7.0 Hz), 2H!, 4.10 (q, J=7.0 Hz, 2H), 7.3-7.5 (m, 3H) IR (neat, cm⁻¹): 1760-1720, 1430, 1380, 1230, 1190, 1120, 790

EXAMPLE 39

Production of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole (Compound 160)

In acetonitrile, were mixed and stirred 0.49 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, 0.3 g of potassium carbonate, and 1.9 g of 1,2-dibromoethane at 80° C. for one hour. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively,dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography to obtain 1.04 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.

Melting point: 60-61° C.

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm): 3.63 (t, J=6.5 Hz, 2H), 4.77 (t, J=6.5 Hz, 2H), 7.3-7.5 (m, 3H) IR (KBr, cm⁻¹): 1485, 1430, 1410, 1360, 1290, 1245, 790

EXAMPLE 40

Production of 3-(2,6-dichlorophenyl)-4- 2-(N-methyl-N-propylamino)ethoxy!-1,2,5-thiadiazole (Compound 161)

In dimethoxyethane, were mixed and stirred 0.35 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazol e, 0.3 g methylpropylamine at 50° C. for 6 hours. The reaction mixture was concentrated, and was purified by silica gel chromatography to obtain 0.2 g of 3-(2,6-dichlorophenyl)-4- 2-(N-methyl-N-propylamino)ethoxy!-1,2,5-thiadiazole.

Oily matter

¹ H-NMR (Solvent: CDCl₃, Unit: δ ppm) 0.81 (t, J=7.5 Hz, 3H), 1.41 (sextet, J=7.5 Hz, 3H), 2.25 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 4.53 (t, J=6.0 Hz, 2H), 7.2-7.45 (m, 3H) IR (neat, cm⁻¹): 3000-2700, 1520, 1490, 1430, 1245, 1025, 790

EXAMPLE 41

Virucidal test aqainst HIV:

In RPMI1640 culture medium containing 20 mM HEPES buffer solution, 10% bovine fetus serum, and 20 μg/mL gentamycin, 3×10⁴ cells of MT-4 (which will be killed by infection with HIV) were infected with HIV at a rate of 0.02 HIV per cell. To the fractions of the culture, predetermined portions of a sample containing the thiadiazole derivative of the compound No. shown in Table 27 and 28 were added, and the culture fractions were incubated at 37° C. After incubation for 5 days, living cells were measured by the MTT method to derive the compound concentration (EC₅₀) which is effective to protects 50% of the MT-4 cells from death by HIV. Separately, the MT-4 cells were incubated in the same manner without infection by HIV, and the compound concentration (CC₅₀) which causes death of 50% of the MT-4 cells. The ratio of CC₅₀ /EC₅₀ is the selectivity index (S.I.). The results are shown in Tables 27 and 28.

                  TABLE 27                                                         ______________________________________                                         Compound   EC.sub.50     CC.sub.50                                             No.        (μg/ml)    (μg/ml)                                                                             S. I.                                         ______________________________________                                          21        0.15          36      240                                            22        0.021         22      1048                                           70        0.026         9.4     362                                            71        0.002         4.7     2350                                           87        0.003         23      7667                                           91        0.063         9.1     144                                            93        1.1           65      59                                             99        0.008         22      2750                                          127        1.5           31      21                                            128        0.19          9.2     48                                            130        0.014         14      1000                                          131        0.29          5.4     19                                            138        1.1           9.9     9                                             145        0.07          2.7     39                                            146        0.3           1.9     6                                             149        1.7           8.6     5                                             155        0.37          >100    >270                                          156        1.8           43      24                                            157        0.36          46      128                                           159        2.2           11      5                                             160        0.32          4.8     15                                            161        0.8           8.3     10                                            195        1.5           37      25                                            ______________________________________                                    

                  TABLE 28                                                         ______________________________________                                         Compound  EC.sub.50     CC.sub.50                                              No.       (μg/ml)    (μg/ml)                                                                             S. I.                                          ______________________________________                                         202       2.5           18      7                                              218       0.38          64      168                                            219       0.018         46      2556                                           220       3.5           63      18                                             222       1.4           >100    >71                                            223       2.6           >100    >38                                            224       0.13          50      385                                            ______________________________________                                    

Industrial applicability:

The arylthiadiazole derivative represented by General Formula I! or II! their salts exhibit viricidal effect, and is useful as a viricide. 

What is claimed is:
 1. An arylthiadiazole derivative represented by General Formula, or a salt thereof: ##STR236## where Y¹ is an oxygen atom or a sulfur atom;W is an oxygen atom or a sulfur atom; one of R¹, R², and R³ is an amino group which may be substituted by one or two independent alkyls of 1-6 carbons; a carboxyl group; a carbonyl group which is substituted by an alkoxyl of 1-4 carbons; a carbamoyl group which may be substituted by one or two independent alkyls of 1-6 carbons; a cyano group; or an alkyl group of 1-6 carbons which is substituted by a hydroxyl, an alkoxyl of 1-4 carbons, an alkoxyl of 1-4 carbons (which is further substituted by another alkoxyl of 1-4 carbons), or a silyloxy (which is substituted by three independent alkyls of 1-6 carbons); the other two of R¹, R², and R3 are independently a hydrogen atom; a halogen atom; an alkyl group of 1-6 carbons which may be substituted by a hydroxyl, an alkoxyl of 1-4 carbons, an alkoxyl of 1-4 carbons (which is further substituted by another alkoxyl of 1-4 carbons), or a silyloxy (which is substituted by three independent alkyls of 1-6 carbons; a trifluoromethyl group; an alkoxyl group of 1-4 carbons; a carboxyl group; a carbonyl group which is substituted by an alkoxyl of 1-4 carbons; a carbamoyl group which may be substituted by one or two independent alkyls of 1-6 carbons; a cyano group; a hydroxyl group; a hydroxymethyl group; a nitro group; or an amino group which may be substituted by one or two independent alkyls of 1-6 carbons; R⁴, and R⁵ are independently a hydrogen atom, an alkoxyl group of 1-4 carbons, an alkyl group of 1-6 carbons which may be substituted by an alkoxyl of 1-4 carbons, a hydroxyl, a cyano, a carboxyl, a carbamoyl, a carbonyl (substituted by alkoxyl of 1-4 carbons), or a group of ##STR237## or R⁴ and R⁵ are linked together to form a group of ##STR238## R⁶, R⁷, and R⁸ are independently a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbons, or an alkoxyl group of 1-4 carbons; R⁹, and R¹⁰ are independently a hydrogen atom, or an alkyl group of 1-6 carbons; E is a --CH₂ -- group, or an oxygen atom; and n¹ is an integer of 0 to
 2. 2. An arylthiadiazole derivative represented by General Formula below, or a salt thereof: ##STR239## where R⁹, and R¹⁰ are independently a hydrogen atom, or an alkyl group of 1-6 carbons;R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group; R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group (which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons).
 3. An arylthiadiazole derivative represented by General Formula below, or a salt thereof: ##STR240## where n³ is 0 or 1; W is an oxygen atom or a sulfur atom;R⁴, and R⁵ are independently a hydrogen atom, an alkoxyl group of 1-4 carbons, an alkyl group of 1-6 carbons which may be substituted by an alkoxyl of 1-4 carbons, a hydroxyl, a cyano, a carboxyl, a carbamoyl, a carbonyl substituted by alkoxyl of 1-4 carbons, or a group of ##STR241## or R⁴ and R⁵ linked together to form a group of ##STR242## R⁶, R⁷, and R⁸ are independently a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbons, or an alkoxyl group of 1-4 carbons; R⁹, and R¹⁰ are independently a hydrogen atom, or an alkyl group of 1-6 carbons; E is a --CH₂ -- group, or an oxygen atom; and n¹ is an integer of 0 to 2; and R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group.
 4. An arylthiadiazole derivative represented by General Formula below, or a salt thereof: ##STR243## where Y¹ is an oxygen atom or a sulfur atom;W is an oxygen atom or a sulfur atom; R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group; R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons; and R¹⁸ is an alkyl group of 1-6 carbons which is substituted by a hydroxyl, a cyano, a carboxyl, a carbamoyl, or a carbonyl substituted by an alkoxyl of 1-4 carbons.
 5. An arylthiadiazole derivative represented by General Formula below, or a salt thereof: ##STR244## where Y¹ is an oxygen atom or a sulfur atom;n² is 1 or 2; R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group; R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group (which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons); and R¹⁹ is a hydrogen atom, or an alkyl group of 1-6 carbons which may be substituted by an alkoxyl of 1-4 carbons.
 6. An arylthiadiazole derivative represented by General Formula below, or a salt thereof: ##STR245## where R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group; andn³ is 0 or 1 provided that R¹¹, R¹², and R¹³ are not simultaneously a hydrogen atom when n³ is
 0. 7. A virucidal composition, comprising a pharmaceutically acceptable carrier and an arylthiadiazole of General Formula or a salt thereof as an active ingredient: ##STR246## where R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group;A is a group of ##STR247## where R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group (which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons); R¹⁵, and R¹⁶ are independently a hydrogen atom, a halogen atom, an alkoxyl group of 1-4 carbons, a nitro group, or an alkyl group of 1-6 carbones which may be substituted with a halogen; R¹⁷ is a halogen atom, or Y² --R¹⁹ ; R¹⁸ is an alkyl group of 1-6 carbons which is substituted by a hydroxyl, a cyano, a carboxyl, a carbamoyl, or a carbonyl substituted by an alkoxyl of 1-4 carbons; R¹⁹ is a hydrogen atom, or an alkyl group which may be substituted by an alkoxyl of 1-4 carbons; J is --CH═, or --N═; n² is 1 or 2; n³ is 0 or 1; Y² is an oxygen atom, a sulfur atom, or --NR¹⁴ --; R⁴, R⁵, R⁹, R¹⁰, R¹⁴, Y¹, and W are the same as defined above.
 8. A virucidal composition, comprising a pharmaceutically acceptable carrier and a virucidally effective amount of the arylthiadiazole derivative of claim 1 or a salt thereof.
 9. A virucidal composition, comprising a pharmaceutically acceptable carrier and a virucidally effective amount of an arylthiadiazole derivative of General Formula or a or a salt thereof: ##STR248## where R¹¹, R¹², and R¹³ are independently a hydrogen atom, a halogen atom, an alkyl group of 1 to 6 carbons, a trifluoromethyl group, an alkoxyl group of 1-4 carbons, a hydroxyl group, or a nitro group;A is ##STR249## where Y¹ is an oxygen atom or a sulfur atom; n² is 1 or 2; R¹⁷ is a halogen atom, or Y² --R¹⁹ ; Y² is an oxygen atom, a sulfur atom, or --NR¹⁴ --; R¹⁴ is a hydrogen atom, an alkyl group of 1-6 carbons, or a phenyl group (which may be substituted by a halogen, an alkyl of 1-6 carbons, or an alkoxyl of 1-4 carbons); and R¹⁹ is a hydrogen atom, or an alkyl group which may be substituted by an alkoxyl of 1-4 carbons. 